The candidate for this Mentored Career Development Award has as long-term goals to: 1) increase her exposure, experience and credibility in vascular physiology as it relates to stroke;2) obtain formal and informal training experiences that are essential to developing a long-term plan of study in rehabilitation research;and 3) execute and expand her comprehensive training program into an independent research career and submit an R01 application. The candidate's immediate goals that support her long-term goals will be to focus on: 1) obtaining a better understanding of vascular physiology (through courses and lab experiences) to understand the mechanistic vascular changes that may occur as a result of an acute stroke;2) acquiring the essential skills to conduct experiments and data analysis for flow-mediated dilation (FMD), Doppler ultrasound and the specialized, vascular wall tracking software;3) understanding how aerobic exercise early in stroke rehabilitation reduces vascular dysfunction;and 4) gathering results and pilot data to become an independent investigator on an R01 submission. The mentorship, training plan and environment that the candidate will have access to are robust and will ensure successful career development. The mentors for this Career Development Award have the background and experience that is complementary to the candidate's and they are committed to helping her succeed and meet her goals. Dr. Billinger's mentors have experience and a track-record of NIH funding, numerous publications and a history of mentoring junior faculty/researchers. Each mentor uniquely contributes to the candidate's scientific and career growth towards independence. Dr. Nudo, the primary mentor, will help the candidate with understanding brain physiology, the cascade of cerebral cellular events that occur after stroke, grantsmanship, improving scientific writing skills for high-impact journal submissions and NIH grants, and conducting mechanistic, hypothesis driven research. Dr. Dengel, co-mentor, will be instrumental for learning how to perform FMD techniques, using Doppler ultrasound for vascular scanning and interpreting findings using electronic vessel-wall tracking software. Dr. Dawn, co-mentor, will provide lab experiences and research discussions on vascular physiology, blood flow, and autonomic control. He will facilitate a productive learning environment between the candidate and the vascular sonographers. Dr. Wood, co-mentor, will provide lab experiences and mentorship regarding vascular regulation and benchtop techniques for identifying mechanisms related to reduced blood flow, hypoxia and vascular dysfunction. Dr. Billinger will be using the ELISA techniques in Dr. Wood's lab for identifying the pro-inflammatory in plasma. Dr Rymer, co-mentor, will ensure access to the stroke patient population and resources to conduct the experiments at the hospital (St. Luke's Brain Institute). She has been part of several clinical trials and can assist the candidate with approaches and problem-solving on recruitment, consenting, and drop-outs. Research Plan: Individuals with chronic stroke demonstrate reduced blood flow in the hemiparetic limb. A better understanding of mechanistic factors that influence vascular regulation after stroke could lead to innovative rehabilitation strategies that diminish disability and improve functional outcomes. Pro-inflammatory markers are released after stroke as a result of the brain injury. The pro-inflammatory markers enter the peripheral vascular system within 24 hours post-stroke. Cytokines (TNF-a, IL-6) and vascular adhesion molecule (VCAM-1) are pro-inflammatory markers that, when present in the vascular system, can reduce production and/or release of nitric oxide, a potent vasodilator. Nitric oxide is needed for vessel dilation to occur in order to accommodate increased blood flow during periods of exercise. Although people post-stroke demonstrate altered vascular function, pilot work suggests exercise can improve blood flow in the hemiparetic limb. The candidate will recruit individuals after an acute stroke to examine the relationship between pro-inflammatory markers and vascular function (using flow-mediated dilation). Plasma samples will be analyzed to quantitatively determine the amount of pro-inflammatory markers in the plasma. Doppler ultrasound and specialized vessel wall tracking software will be used to assess vascular function. In the most innovative aspect of the project, the candidate will also explore the role of an aerobic exercise intervention during stroke rehabilitation. The candidate believes that the exercise intervention will down-regulate the effect of pro-inflammatory markers and improve vascular regulation. The candidate plans to use the results from these experiments as pilot data for a larger clinical trial. However, before a clinical trial is undertaken, it is important and essential that one understands the role of pro-inflammatory markers and vascular function during stroke recovery. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of death and disability for older adults in the United States with approximately 795,000 new or recurrent strokes occurring each year. Elevated levels of inflammatory markers have been predictive of poor outcomes after stroke. This project will explore the role of circulating inflammatory markers in the blood and the impact of these markers on vascular health. The candidate will also use an aerobic exercise intervention to evaluate whether exercise decreases the level of inflammatory markers in the blood and positively affects vascular function in stroke survivors. This study will further our understanding of the physiologic mechanisms that affect vascular function after stroke and lead to effective rehabilitation strategies in reducing disability from this devastating event.